2.b. Opportunities The NWRCE is primed to produce high quality research, training, and development programs in the biology of Gram-negative bacteria relevant to biodefense and emerging infectious diseases. During the first grant period, the Center has become an efficient engine of basic science, translational research, and product development. As a new program, the RCEs underwent a natural startup phase, but this period is now over and the NWRCE has implemented all its functional elements. Using a combination of modern technologies, new knowledge of basic mechanisms of bacterial pathogenesis, and the wide availability of genome sequences, the NWRCE is capable of driving infectious disease research at a rapid pace. By using a high throughput approach in which large amounts of relevant data can be quickly generated, assessed for potentially practical benefits, and shared among a consortium of skilled investigators, the NWRCE is designed to produce knowledge and products of practical benefit to infectious diseases of national significance. Growth of the NWRCE at the University of Washington would further capitalize on the vibrant and expanding research environment at the UW. The University of Washington is one of the most best-funded public biomedical research institutions in the nation, and the research infrastructure is continuing to undergo expansion. The UW is creating new research space at its South Lake Union site in Seattle, which includes BSL-3 facilities. This space could potentially be used for recruitments in new research areas that would add additional strength, capacity, and flexibility to the NWRCE. Recently, the new Department of Global Health was formed, chaired by King Holmes who serves on the NWRCE External Advisory Board. Large-scale renovation projects in the Health Sciences Building, which houses the Select Agent Laboratory and a number of Center investigators, are underway as part of a multi-year program of research space modernization. Seattle is a unique environment with many institutions including the Gates Foundation, Program for Appropriate Technology in Health (PATH), Infectious Disease Research Institute (IDRI), the Institute for Systems Biology (ISB), Seattle Biomedical Research Institute (SBRI) Virginia Mason Reseach Center, the Fred Hutchinson Cancer Centter, as well as the University of Washington, all of which make infectious diseases and immunological responses to pathogens a major research priority. The NWRCE has the opportunity to further develop collaborations with regional, national, and international entities. As described in the Overview, the NWRCE has investigators and collaborators affiliated with the following participating institutions: [unreadable] University of Washington School of Medicine Seattle, WA [unreadable] VA Puget Sound Medical Center, Seattle WA [unreadable] Harborview Medical Center, Seattle, WA [unreadable] The Institute for Systems Biology, Seattle, WA [unreadable] Children's Regional Medical Center, Seattle, WA [unreadable] NIAID Rocky Mountain Laboratories, Hamilton, MT [unreadable] University of Idaho, Moscow, ID [unreadable] University of Oregon, Eugene, OR [unreadable] Oregon Health &Sciences University, Portland, OR [unreadable] University of Maryland, Baltimore, MD [unreadable] University of Louisville, Louisville, KY [unreadable] Public Health Seattle/King County [unreadable] University of Victoria, British Columbia, Canada [unreadable] Mahidol University, Bangkok, Thailand [unreadable] Umea University, Umea, Sweden [unreadable] Institute de Diagnostico y Referenda Epidemiologicos, Mexico City, Mexico There are a number of other entities in Region X which provide further opportunities for interactions with the NWRCE, including the previously mentioned Department of Global Health, the Institute for Health Metrics and Evaluation, and the Gates Foundation. The NWRCE has previously sponsored developmental projects at the University of Alaska-Fairbanks and Oregon State University and will continue these outreach efforts. External Advisory Board member Guy Palmer is appointed at Washington State University in Pullman, WA, and the Directors have also interacted with Washington State University Veterinary Microbiology &Pathology faculty member Dr. Thomas E. Besser. These interactions will be strengthened for the purposes of adding zoonotic disease expertise to the NWRCE. The three foreign institutions listed above comprise the NWRCE's foreign collaborators. Established during the supplemental year, these collaborations provide access to international strain collections, clinical information, and expertise from endemic areas. Dr. Sharon Peacock with Mahidol University will be working with NWRCE investigators to provide an extensive clinical repository of Burkholderia pseudomallei as well as her scientific expertise as a noted researcher on melioidosis, the disease caused by B. pseudomallei. Dr. Anders Sjostedt of Umea University will provide isolates of Francisella from northern Europe and Asia. Dr. Celia Alpuche Aranda of the Institute de Diagnostico y Referenda Epidemiologicos (the Mexican equivalent of the US Centers for Disease Control and Prevention) will provide strains and clinical information from current and historic outbreaks of Shigella dysenteriae and other emerging and outbreak-related Gram-negative strains. These collaborations will increase the profile of the NWRCE and the RCE network internationally, and potentially foster additional interactions with other officials and investigators at these international sites of relevance to disease emergence on the West Coast of the United States. These strains from foreign sites will be utilized extensively by multiple projects, and will provide a reference source for comparison of new outbreaks, either naturally occurring or man-made, and as such will contribute to our emergency response capacity. The NWRCE will expand its interactions with federal agencies, intramural research laboratories, state and local health departments, and the private sector. As a result of the research emphasis on infectious disease, select agents, and national biodefense needs, NWRCE Directors and Investigators have access to and a working dialogue with federal officials and agencies, and have, over the past five years, advised and interacted with officials from the Department of Justice, Department of Defense, Public Health Service, USDA, FDA, CDC, and the Executive Branch. Examples of such interactions include meeting with Colonel Ralph Erickson, Director of GEIS (Global Emerging Infections System DoD), participating in a Defense Threat Reduction Agency subcontract (HDTRA-07-9-0003), and attending briefings by Joint Terrorism Task force agents (FBI/DoJ). The Emergency Response Director has advised the White House on the impact of a possible H5N1 flu pandemic. The NWRCE Director also participated in a meeting advising the FBI on its relationship with academic institutions with respect to nuclear, technological and biological threat risk. The Directors have had communication with Dick Smith of the Pacific Northwest National Laboratories (PI of High Throughput Proteomics), and will continue to explore ways in which the PNNL and the NWRCE may interact. A number of NWRCE personnel, most notably Emergency Response director Jeff Duchin MD, have CDC experience and have facilitated communication with that agency on several occasions. Dr. Duchin also has extensive connections in the regional public health sector as Chief of Communicable Diseases for Public Health - Seattle &King County. He has helped to facilitate contact with public health laboratories in the city, state, region, and nation. Additionally, the NWRCE has participated in several grant applications with biotechnology companies (Implicit Biosciences and Micronics, Inc.). In both of these cases the NWRCE was sought out because of its select agent capabilities and expertise. These interactions have been quite fruitful and will likely increase as the Center moves into new research areas, adds new investigators, and moves products into development. The NWRCE will expand its capacity to form part of a national resource in proteomics, genomics, and bioinformatics for the study of Gram-negative infections. The NWRCE created capacity in these methodologies and applied them to the study of basic science, proteomics, and genomic aspects of Gramnegative bacteria. This effort has produced information and databases of use to biodefense/EID researchers, and infectious disease investigators in general. The NWRCE will continue to use its specific focus and economy of scale to integrate the data from throughout the infectious disease field, the biodefense network, and its own research findings to increase its value as a resource. Efforts such as these can best be catalyzed and funded through a cooperative mechanism such as the national RCEs. In addition, the physical resources generated by NWRCE research (instrumentation, mutant libraries, chemical compound screening &libraries, and unique transgenic mouse strains) will enhance and accelerate research outside of the Center. The NWRCE will function in a complementary fashion with other efforts in the region to promote national research efforts in biodefense and emerging infectious diseases. Within Region X, over a billion dollars in NIH funding is currently awarded. NIAID alone sponsors 315 research grants in Washington, Oregon, Idaho, and Alaska, and 44 of them are awarded for study of NIAID Category A - C Priority Pathogens. NIH funding for infectious disease research is also granted to researchers through other institutes, such as NHLBI, NIDDK, and NIGMS. This scientific community combines to create a nationally significant infrastructure of infectious disease centered on the University of Washington. Another significant ongoing effort is the bacterial pathogenesis work being done at Rocky Mountain Laboratories in Montana. The NWRCE has established collaborations with two investigators at this NIH/NIAID facility, Dr. Joe Hinnebusch and Dr. Jean Celli, providing expertise and experimental models for V. peso's and F. tularensis, respectively. This laboratory is completing renovations to create BSL-4 laboratories;although the NWRCE has no current plans to study Risk Group 4 agents, these facilities may be available in such an event. This collaboration provides an excellent opportunity for cooperative, coordinated research with the scientists and facilities at RML. The strengths of RML in both Gram-negative and Gram-positive infections and vector borne diseases complement the efforts of the NWRCE, and an ongoing relationship between the institutions would create benefits for both (see Letters of Support). The NWRCE will continue to translate basic biological information into useful therapeutics and other countermeasures. The NWRCE is structured to allow rapid translation of basic discoveries into practical therapeutics. In the first grant period, the center advanced two vaccine candidates to animal trials and has advanced several lead antimicrobial compounds. In response to NIAID program requirements, this application refocuses the product development program toward the creation of therapeutics that function across a broad host range. These programs are already primed in terms of biological target identification, compound screening &medicinal chemistry, and animal models of efficacy. The NWRCE will become an important resource and maintain databases of information about currently active bacterial pathogens and begin to understand pathogen diversity and the diversity of human responses to these pathogens. The challenge for the 21st century is to understand and integrate pathogen and human diversity to understand and predict infectious disease outcomes. It is a goal of the NWRCE - and in part its raison d'etre - to begin this effort and provide leadership in this area. Drs. Olson and Miller have been leaders in defining genotypes and phenotypes of natural isolates of P. aeruginosa from cystic fibrosis patients. Dr. Aderem, Martin, Wilson, Hajjar, Ernst, Miller, and Wurfel have been among the leaders defining variation in human responses to Gram-negative agents.